ABSTRACT
Genome-wide association studies have identified risk loci linked to inflammatory bowel disease (IBD)1-a complex chronic inflammatory disorder of the gastrointestinal tract. The increasing prevalence of IBD in industrialized countries and the augmented disease risk observed in migrants who move into areas of higher disease prevalence suggest that environmental factors are also important determinants of IBD susceptibility and severity2. However, the identification of environmental factors relevant to IBD and the mechanisms by which they influence disease has been hampered by the lack of platforms for their systematic investigation. Here we describe an integrated systems approach, combining publicly available databases, zebrafish chemical screens, machine learning and mouse preclinical models to identify environmental factors that control intestinal inflammation. This approach established that the herbicide propyzamide increases inflammation in the small and large intestine. Moreover, we show that an AHR-NF-κB-C/EBPß signalling axis operates in T cells and dendritic cells to promote intestinal inflammation, and is targeted by propyzamide. In conclusion, we developed a pipeline for the identification of environmental factors and mechanisms of pathogenesis in IBD and, potentially, other inflammatory diseases.
Subject(s)
Environment , Herbicides , Inflammation , Inflammatory Bowel Diseases , Intestines , Animals , Mice , Inflammation/chemically induced , Inflammation/etiology , Inflammation/immunology , Inflammation/pathology , Inflammatory Bowel Diseases/chemically induced , Inflammatory Bowel Diseases/etiology , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/pathology , Zebrafish , Machine Learning , Databases, Factual , Disease Models, Animal , Intestines/drug effects , Intestines/immunology , Intestines/metabolism , Intestines/pathology , NF-kappa B , CCAAT-Enhancer-Binding Protein-beta , Receptors, Aryl Hydrocarbon , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Dendritic Cells/drug effects , Dendritic Cells/immunology , Dendritic Cells/metabolism , Herbicides/adverse effectsABSTRACT
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor initially identified as the receptor for dioxin. Almost half a century after its discovery, AHR is now recognized as a receptor for multiple physiological ligands, with important roles in health and disease. In this review, we discuss the role of AHR in the gut-brain axis and its potential value as a therapeutic target for immune-mediated diseases.
